Identifying germline APOBEC3B deletion and immune phenotype in Korean patients with operable breast cancer

摘要

Background Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3B (APOBEC3B) is implicated in anti-viral immune response and cancer mutagenesis. Germline APOBEC3B deletion is associated with increased susceptibility to breast cancer. We aimed to evaluate the association between germline APOBEC3B deletion and clinical phenotypes of breast cancer in Korean patients with operable breast cancer. Methods Mononuclear blood cell DNA of 103 patients with operable breast cancer was collected at Seoul National University Bundang Hospital in 2009. The DNA was sequenced to analyze APOBEC3B deletion status. Further, tumor-infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PD-L1) expression in tumor cells were measured using immunohistochemistry. Results Median age of breast cancer diagnosis was 46 (25-72). In APOBEC3B deletion analysis, 10 (9.7%), 36 (35.0%), and 57 (55.3%) patients were identified as two-copy deletion (A3B(del/del)), one-one copy deletion (A3B(del/wt)), and no deletion (A3B(wt/wt)), respectively. For other cancer susceptibility gene alterations, 9 (8.7%) patients were identified as pathogenic variants: RAD51D (n = 1), GJB2 (n = 1), BRCA1 (n = 1), BRCA2 (n = 2), ATM (n = 1), USH2A (n = 1), RET (n = 1), BARD1 (n = 1). We observed no significant association between germline APOBEC3B deletion with any clinicopathologic features of breast cancer, such as age, family history of cancer, and bilateral breast cancer. Further, according to follow-up observations, APOBEC3B deletion was not predictive of disease-free survival. In ER+ subtype, a trend toward better survival was observed in patients with A3B(del/del)genotype as compared to patients with A3B(del/wt)and A3B(wt/wt)genotype (log-rank,P = 0.25). In patients with sufficient tumor samples for the assessment of TIL (n = 63) and PD-L1 (n = 71), the A3B(del/del)genotype was significantly associated with high TILs (> 10%) than other tumor genotypes (6/7 patients in A3B(del/del)vs. 13/24 in A3B(del/wt)vs. 15/32 in A3B(wt/wt): Fisher's exact test,P = 0.029). However, PD-L1 expression was not associated with APOBEC3B deletion status (1/7 patients > 1% PD-L1 in A3B(del/del)vs. 4/26 in A3B(del/wt)vs. 8/38 in A3B(wt/wt):P = 0.901). Conclusion We identified germline APOBEC3B deletion in 9.7% of Korean patients with operable breast cancer. The relationship between A3B(del/del)genotype and high TILs suggests that patients carrying this genotype could be potential candidates for immunotherapy.